The present invention relates to infusion devices for introducing fluids into a patient and, more particularly, to an infusion device and method of infusing minute volumes of liquid at extremely low flows into the brain of a patient.
There are certain procedures carried out on a patient where extremely minute, sub-milliliter amounts of fluids or suspensions are directly infused into the brain of the patient and such fluids can include therapeutic drugs or biological material including peptides, proteins, viral vectors, DNA, RNA and other nucleic acids, lipids and liposomes, polymers, dendrimers and the like or combinations thereof The fluids are infused into a particular target area within the brain that may range from about 1 mm3 to as large as several cubic centimeters. In any event it is extremely important to accurately reach the target area with the particular fluid and to infuse the fluid into the patient at that desired location, adequately covering the desired area in a controlled fashion.
Since the actual infusion is of minute quantities of fluid and with flow rates of the infused fluid very slow, i.e. several nanoliters to up to 1 ml or more infused at a rate of, for example, 1.0 nl/min to several microliters/min, the infusion device must be very minute and must be accurately placed at or proximate to the target area. Additionally, since the infusion device is actually located within the brain, it is desirable that the end of the device that is infusing the fluid be somewhat flexible and preferably move with the brain during respiration since a rigid device can cause trauma to the brain tissue and/or brain hemorrhage. This is particularly true since the infusion device may be implanted to remain over a substantial period of time extending at least several hours to days or more. It is also desirable to have a device which is sufficiently resilient that it can be secured with a fixation device to prevent movement away from the target without damaging the catheter infusion system. It is also desirable to have a system which can be imaged to confirm the location in the brain and to ensure that the catheter has not moved from the target at any point.
Accordingly, one current method of infusing such fluids is to utilize a radioopaque catheter having an internal diameter of about 1.3 mm. into the brain and attach an infusion pump to the catheter. The catheter is normally introduced by means of a relatively rigid stylet that is inserted into the brain to the target area and the catheter then threaded over the stylet with the stylet being removed after the distal end of the catheter is located at the target area. Such catheter has, however, a rather large dead space due to the very dimensions of that catheter. This large dead space limits reliability and reproducibility of infusions, particularly for small volumes of fluid, due to the large errors and insensible losses inherent in catheters with dead spaces which are significantly greater that the actual volume of fluid to be infused. In addition, large catheters cause significant damage to the brain in the area of infusion. This not only can confound therapeutic results, it can also limit the effectiveness and reliability of the infusion. For example, larger catheters in animal subjects have been found to result in more limited diffusion in the brain compared with smaller catheters. This likely is due to the fact that damage from a larger catheter causes fluid to pool in the cavity caused by the damage, while infusing through intact brain via a smaller catheter causes the fluid to diffuse more reliably in the natural interstitial space of normal tissues.
This creates a dilemma, however. Although fine catheters are desirable, very fine systems do not usually have the resiliency or strength to withstand long term use. This would be particularly true for catheters which would be externalized and attached to an infusion pump, since these would be particularly subject to damage by the patient or by routine healthcare workers. Clamping very fine catheters in fixation devices, usually requiring catheters to be bent at extreme angles, would also likely break or obstruct a fine catheter. Similarly, an extremely fine catheter is difficult to visualize by imaging, even when impregnated with a contrast agent, due to resolution limits of current imaging systems.
Therefore, there is a need for a catheter system which has a sufficiently small diameter at the distal, infusion end to minimize local tissue trauma, with a very small dead space yet with the strength of a larger catheter to prevent breakage and permit fixation, and with the ability to visualize the catheter by imaging. A system harboring all of these features currently does not exist. Current systems for infusion are largely designed for infusion into fluid channels, such as intravascular or intrathecal infusion, and thus are limited in one of more of the criteria outlined above. What is described in this application is a novel concept for an infusion system which incorporates all of these features which are key to optimizing infusion of small volumes of fluid directly into solid tissue targets.